Method for preparing repaglinide amine and intermediate thereof
A technology of repaglinide and time, which is applied in the field of preparation of repaglinide and its intermediates, can solve the problems of harsh reaction conditions, poor safety, and low yield, and achieve easy purification, easy operation, and post-processing Handle simple effects
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Embodiment 1
[0038]
[0039]In a 500ml dry four-necked flask, add 250ml of anhydrous tetrahydrofuran and (R)-N-p-toluenesulfonyl protected o-chlorophenyl aza three-membered ring 15.4g (50mmol), cuprous iodide 15g (79mmol), Add 60ml of 1M isopropylmagnesium chloride tetrahydrofuran solution dropwise at 25°C. After the addition is complete, stir until TLC shows that the reaction is complete. Pour into ice water to extract the reaction, separate liquids, extract the aqueous phase, combine the organic phases, wash, dry and concentrate, and the remaining The product was recrystallized to obtain 15 g (43 mmol) of the ring-opened product, which was directly used in the next reaction. Dissolve 15g (43mmol) of the ring-opened product in 250ml of dimethyl sulfoxide, add 15g (109mmol) of potassium carbonate and 15g (176mmol) of piperidine, heat and reflux until TLC shows that the raw materials disappear, pour into ice water after cooling, and extract. Combine the organic phases, dry and concentrat...
Embodiment 2
[0044]
[0045] In a 500ml dry four-necked flask, add 250ml of anhydrous diethyl ether and (R)-N-p-toluenesulfonyl protected o-chlorophenyl aza three-membered ring 15.4g (50mmol), cuprous iodide 15g, under 25 degrees Add 60ml of 1M isopropylmagnesium chloride ether solution dropwise, stir until TLC shows that the reaction is complete, pour into ice water to extract the reaction, separate liquids, extract the water phase, combine the organic phases, dry and concentrate after washing, and recrystallize the residue 15 g of the ring-opened product was obtained, which was directly used in the next reaction. Dissolve 15g of the ring-opened product in 250ml of dimethyl sulfoxide, add 15g of potassium carbonate and 15g of piperidine, heat and reflux until TLC shows that the raw materials disappear, pour into ice water after cooling, extract, combine the organic phases, dry and concentrate after washing, Dissolve the residue in methanol, add 24g of magnesium powder, heat to reflux, ...
Embodiment 3
[0048]
[0049] In a 500ml dry four-necked flask, add 250ml of anhydrous tetrahydrofuran and (R)-N-p-toluenesulfonyl protected o-chlorophenyl aza three-membered ring 15.4g (50mmol), cuprous cyanide 15g (167mmol), Add 60ml of 1M isopropylmagnesium chloride tetrahydrofuran solution dropwise at 25°C. After the addition is complete, stir until TLC shows that the reaction is complete. Pour into ice water to extract the reaction, separate liquids, extract the aqueous phase, combine the organic phases, wash, dry and concentrate, and the remaining The product was recrystallized to obtain 15 g of the ring-opened product, which was directly used in the next reaction. Dissolve 15g of the ring-opened product in 250ml of dimethyl sulfoxide, add 15g of potassium carbonate and 15g of piperidine, heat and reflux until TLC shows that the raw materials disappear, pour into ice water after cooling, extract, combine the organic phases, dry and concentrate after washing, Dissolve the residue in...
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